We hypothesized that Natural Killer (NK) cells would have other receptors for target cells besides the previously identified Killer Inhibitory Receptors (KIR). The fact that virtually all NK cells had transcripts for NKG2 family members led us to focus on this gene family. Initially we showed that most NK cells express a member of the NKG2 family on the cell surface paired with CD94. The NKG2 family member determined whether the NK cell was inhibited or activated by the presence of class I on the surface of target cells. Most recently, we have shown that the CD94/NKG2 receptor can recognize HLA-E, a non-classical, class I molecule with no previously ascribed function. This recognition was shown to depend on the presence of particular signal peptide from classical class I molecules being bound to the peptide binding groove of HLA-E. Whether CD94/NKG2 can also recognize classical class I molecules or HLA-E in association with other peptides beside the class I signal peptides is being determined. We are also investigating what purpose the expression of two completely different types of receptors for class I molecules, some of each other being inhibitory and some activating, serves for NK cell function. The mechanism for triggering the NK cell lytic and inhibitory pathways through the CD94/NKG2 receptor, along with what role this receptor plays in vivo to control such diseases as cancer and viral infections is being investigated.